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Time to Stop (TTS) Trial: a trial to investigate early antiepileptic drug withdrawal after pediatric epilepsy surgery

Condition category

Nervous System Diseases

Date applied

28/03/2013

Date assigned

08/05/2013

Last edited

28/10/2015

Prospective/Retrospective

Prospectively registered

Overall trial status

Ongoing

Recruitment status

Recruiting

Plain English Summary

Background and study aims There is no consensus about timing of anti-epileptic drug (AED) withdrawal after pediatric epilepsy surgery. Our previous study of 766 children suggested that early withdrawal does not affect long-term seizure outcome, unmasks incomplete surgical success sooner, and prevents unnecessary AED use in many children. We now aim to demonstrate cognitive and behavioral benefits and improvement of quality of life, and confirm safety of early AED discontinuation in this study.

Who can participate? The Time to Stop trial aims to recruit 180 pediatric patients, aged younger than 16 years, from participating pediatric epilepsy surgery centers in Europe.

What does the study involve? The Time to Stop trial in which an early AED withdrawal group, that starts reduction of AEDs four months after surgery and completes withdrawal within eight months after start of withdrawal, will be compared to a late AED withdrawal group, in which tapering off medication starts at 12 months after surgery and completion should be within 20 months after surgery. The primary outcome measure is attention, as measured by reaction time on CPT (Conner's Performance Test). Other neuropsychological domains will be assessed by standard neuropsychological testing, as part of standard clinical care. Other outcome measures are seizure recurrences, eventual seizure freedom and cure, behavioral changes and quality of life. Patients will be allocated to treatment by concealed randomization (like a coin toss). In both groups, the latest follow-up time point will be 20 months following start of intended withdrawal (i.e. 24 months in the early group, and 32 months in the late withdrawal group), thus the total follow-up duration of being at risk [without drugs] will be identical between groups. Patients will be studied in an outpatient clinical setting.

What are the possible benefits and risks of participating? We hypothesize that the study is beneficial to the patients in the investigational arm, the early withdrawal arm, as they are devoid of medication in an earlier postoperative stage. Their cognitive functions might improve and medication related side effects may be less frequent. With regard to the risk assessment, we have strong arguments - based on our previous large retrospective study in 766 children - to assume that the risk for seizure recurrences in the early withdrawal group will be comparable to the late withdrawal group, as we will exclude patients with known predictors of unfavorable outcome. The recurrences will only occur earlier during follow up. We expect a recurrence rate, comparable to normal clinical practice, of around 30%. Most of the patients will regain seizure freedom after restart of antiepileptic drugs, as shown previously and in accordance to current clinical experience.

Where is the study run from? The Time to Stop trial is set up and led by the University Medical Center Utrecht, The Netherlands.

When is the study starting and how long is it expected to run for? It is anticipated that recruitment will start in the beginning of 2014. The study will run for five years.

Study design

Primary study design

Secondary study design

Trial setting

Trial type

Treatment

Patient information sheet

Not available in web format, please use the contact details below to request a participant information sheet

Condition

Intractable epilepsy

Intervention

The Time to Stop trial will compare an early AED withdrawal group, that starts reduction of AEDs four months after surgery and completes withdrawal within eight months after start of withdrawal, with a late AED withdrawal group, in which tapering off medication starts at 12 months after surgery and completion should be within 20 months after surgery.

Intervention type

Drug

Phase

Not Applicable

Drug names

Primary outcome measures

The primary objective of the study is to assess whether early AED withdrawal improves cognitive function, in terms of attention, information processing- and psychomotor speed, memory, language and IQ/DQ scores. Attention will be the main outcome measure, on which the power calculation is based.

We will assess attention deficits (AD), using a Conner's Performance (Kiddie) test and calculate IQ/DQ scores. The other neuropsychological domains will be assessed by subtests of the intelligence tests. We will compare neuropsychological outcome between the two withdrawal groups at t1 (preoperatively), t2 (at 12 months) and t3 (at 24 months).

Secondary outcome measures

1. To confirm safety, in terms of seizure recurrences, long term seizure freedom and cure, of early AED withdrawal. In the randomized trial we determine long-term seizure outcome and cure at 20 months following intended start of AED reduction (being theoretically 'at risk' during an identical time window in both groups). Seizure freedom will be defined as complete seizure freedom for at least one year [Engel 1(3) of International League Against Epilepsy (ILAE) 1-2(4)], and cure as seizure freedom and AED freedom for at least one year. The existence of seizure recurrences will be measured every time the patient visits her/his epileptologist, and if parents call the hospital to report seizure recurrences. 2. To compare behavioural problems between the two withdrawal groups, parents of participants will, at both postoperative neuropsychological test points, complete a Child Behavior Checklist (CBCL) (12 and 24 months postoperatively)3. To compare quality of life between the two withdrawal groups. Patients will, at both postoperative neuropsychological test points, complete a Pediatric Quality of Life InventoryTM (PedsQL™) and the The Hague Side Effects Scale (HASES) (12 and 24 months postoperatively).

Overall trial start date

01/01/2014

Overall trial end date

01/01/2019

Reason abandoned

Eligibility

Participant inclusion criteria

1. Younger than 16 years at surgery, with focal non-idiopathic epilepsy 2. Native speaker in the language the neuropsychological tests have to be taken3. Be able to perform a Conner's Performance Test preoperatively (generally that means age > 4 yrs, and IQ > 60)4. Underwent intentional curative epilepsy surgery 5. After surgery, the treating physician considers withdrawal of antiepileptic drugs (AEDs), with the intention to completely discontinue medication, at whatever point in time.6. Both the treating physician, the patient, if capable, and the parents agree with randomization in either arm of the study7. Postoperative seizure freedom was achieved (with the exception of so called running down seizures not outlasting longer than two weeks)

Participant type

Patient

Age group

Child

Gender

Both

Target number of participants

180

Participant exclusion criteria

1. A contraindication to be randomized to either of the two withdrawal arms2. The treating physician does not want to discontinue all AEDs within a maximum time frame of eight months as prescribed in the study protocol.3. Multifocal MRI abnormalities, incomplete resection of the anatomical or epileptogenic lesion certified before randomisation (if considered necessary by the treating physician by MRI) and, if a postoperative EEG is performed before randomisation, epileptic EEG abnormalities (these being the most important risk factors of seizure recurrence or unfavourable long-term seizure outcome). 4. Use of more than three AEDs at time of surgery. The reason to choose for a maximum of three AEDs is that clinicians would not want to wait 12 months (the late withdrawal arm) to withdraw the first AED in patients that use so many AEDs. Furthermore, withdrawing AEDs within 8 months seems reasonable and feasible for a maximum of three AEDs.5. Patients who are on a ketogenic diet or have a vagal nerve stimulator implanted.6. If surgery is primarily intended as tumor surgery and not as epilepsy surgery